DOI: https://doi.org/10.22516/25007440.309 Review articles The role of antispasmodics in managing irritable bowel syndrome Valeria Atenea Costa Barney,1* Alan Felipe Ovalle Hernández.1 1 Internal Medicine and Gastroenterology specialist Abstract in San Ignacio University Hospital, Pontificia Universidad Javeriana, Bogotá, Colombia. Although antispasmodics are the cornerstone of treating irritable bowel syndrome, there are a number of an- tispasmodic medications currently available in Colombia. Since they are frequently used to treat this disease, *Correspondence: [email protected] we consider an evaluation of them to be important. ......................................... Received: 26/10/18 Keywords Accepted: 11/02/19 Antispasmodic, irritable bowel syndrome, pinaverium bromide, otilonium bromide, Mebeverin, trimebutine. INTRODUCTION consistency. The criteria must be met for three consecutive months prior to diagnosis and symptoms must have started Irritable bowel syndrome (IBS) is one of the most fre- a minimum of six months before diagnosis. (3, 4) quent chronic gastrointestinal functional disorders. It is There are no known structural or anatomical explanations characterized by recurrent abdominal pain associated with of the pathophysiology of IBS and its exact cause remains changes in the rhythm of bowel movements with either or unknown. Nevertheless, several mechanisms have been both constipation and diarrhea. Swelling and bloating are proposed. Altered gastrointestinal motility may contribute frequent occurrences. (1) to changes in bowel habits reported by some patients, and a IBS is divided into two subtypes: predominance of cons- combination of smooth muscle spasms, visceral hypersen- tipation (20-30% of patients) and predominance of dia- sitivity and abnormalities of central pain processing may rrhea (20-30% of patients). When both constipation and explain abdominal pain, which is an essential part of the diarrhea are combined, it is called mixed IBS (up to 45% of complex of symptoms. (5) patients) and IBS of undetermined type when the pattern of It is estimated that IBS affects 11% of the world’s popu- bowel movements is intermediate and cannot be classified lation. In Europe, Asia and the United States its prevalence as diarrhea or constipation. It is noteworthy that abdominal varies from 10% to 20%. The lowest prevalence in South pain occurring more than once a week plus the temporal Asia (7%) while the highest is in South America (21%). relationship of pain with defecation are what theoretically In Western countries it is twice as frequent in women. (6) differentiates IBS from functional constipation. (2, 3) IBS has a significant impact on health-related quality of According to the Rome IV criteria, IBS is diagnosed by life, results in lower labor productivity, higher absenteeism abdominal pain that recurs at least one day a week plus two and increased use of health care with its attendant costs. In or more of the following: pain is associated with defeca- 2005, direct medical costs attributed to IBS in the United tion; pain is related to a change in the frequency of bowel States were estimated at USD 1.5 to 10 billion per year. (1) movements; and/or pain is related to a change of stool IBS can also affect the doctor-patient relationship since © 2019 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología 267 ineffective control of symptoms can decrease the credibi- also play an important role in the development of visceral lity of doctors and encourage the patient to seek additional hypersensitivity because they produce and release sero- opinions. (7) tonin which activates 5-HT3 receptors located in afferent A heterogeneous group of medications called antispas- sensory neurons. (17) modic or spasmolytic drugs has been used in IBS therapy Abnormalities in colonic motility patterns are characteri- for decades. They act as direct smooth muscle relaxants zed by hyperreactivity due to prolonged increase of colonic (papaverine, mebeverin, peppermint oil), anticholinergic motor activity after meals, increased motor activity in res- agents (butylscopolamine, hioscin, cimetropium bromide, ponse to stressors or cholecystokinin (CCK), and increa- pyrenzepine) or calcium channels blockers (alverine sed motor response to abdominal distention. (18) citrate, ethyl bromide, pinaverium bromide). Their goal is to Visceral hypersensitivity alone is not painful, but it can reduce symptoms caused by defecation through increasing cause abdominal pain in IBS patients due to the effect of colonic transit time, improving stool consistency and/or any intense stimulus such as an exaggerated contraction of reducing stool frequency. (2) The pharmacological action the colon. (19) Nevertheless, it has not been possible to of these agents is not always clear, and their mechanisms establish a clear relationship between visceral hypersen- are often mixed. However, metaanalyses of studies com- sitivity and motility disorders, and these two factors have paring antispasmodics with placebos or other treatments generally been considered to be independent, and both have consistently confirmed the positive effects of these require effective treatment. (20) drugs, and their side effect profiles have been excellent. (8) Voltage Dependent Calcium Channels PATHOPHYSIOLOGY Voltage-dependent calcium channels play a fundamental The pathogenesis of IBS is considered to be multifactorial. role in the intestine and in pharmacological management A history of gastrointestinal infections, colonic or bacterial of IBS. These ionic channels mediate calcium influx in res- flora of an altered small intestine, increased intestinal per- ponse to membrane depolarization, and they regulate intra- meability and immune activation may all play roles in the cellular processes such as contraction, secretion and neu- development of the disease. (9) Signals from the gastroin- rotransmission in a variety of cells. (21) Calcium channels testinal tract are processed in the brain and can influence are classified by their properties and pharmacology. They motility, secretion and immune function. The brain-gut include L-type calcium channels (long duration). They axis is essential for regulation of the gastrointestinal sys- are high conductance channels that produce long-lasting tem, so structural or functional alteration can lead to the depolarization and which are inhibited by dihydropyridine development of disorders such as IBS. (10) Consequently, derivatives (DHP). (22, 23) Currents associated with this psychological factors and chronic stress may also be invol- type of channel are important for muscle and endocrine ved in triggering symptoms. (11) cells in which contraction and secretion of substances are Abnormal intestinal motility and visceral hypersensitivity mediated. (21) remain the main factors in the pathogenesis of the disease. Type N (neuronal) currents are also durable, but require (12) Intraluminal factors such as serine proteases may strongly negative potentials for complete elimination of increase colonic permeability of IBS patients by activating inactivation and strong depolarization for activation. (23) the protease-activated receptor-2. This results in visceral Three other channels have been identified in Purkinje hypersensitivity. (13) Similarly, luminal cysteine ​​proteases cells. Type P currents are blocked by low concentrations of have been shown to increase colonic permeability through ω-agatoxin, while type Q only responds to high concentra- degradation of binding proteins resulting in visceral hyper- tions. Residual currents, which were resistant to all known sensitivity possibly secondary to local microinflammation. calcium blockers at the time of their discovery, were called (14) Immune activation of the colonic mucosa has been type R (resistant). Type T (transient) voltage-dependent found to be significantly greater in IBS patients than in calcium channels are characterized by small and transient healthy controls. (15) In addition, mast cells have been conductance activated by weak depolarization. (23) These implicated in the development of IBS. One study found currents are responsible for modulating the action poten- that the number of mast cells in the colonic mucosa and tial and the performance of pacemakers. the amounts of trypsin and histamine they released were In the 1980s DHP antagonists became the first calcium markedly higher in IBS patients than in controls. (16) Mast antagonists to be used medically. They block L channels cells in the vicinity of nerve endings has been significantly and are used to treat hypertension by exploiting their pro- correlated with the severity and frequency of abdominal perties as vasodilators. (22) Calcium antagonists have no pain and discomfort in IBS patients. Enterochromaffin cells effect on skeletal muscle, but they can have some influence 268 Rev Colomb Gastroenterol / 34 (3) 2019 Review articles on heart muscle through reduction of activity and con- of the days to less than one day per week while the patients duction of pacemakers. Because IBS includes abnormal who took placebos continued to have one to three episodes gastrointestinal motility, calcium antagonists used for car- per week. During the 10-week follow-up period after the diovascular disease appear to have potential for relieving end of treatment, the likelihood of recurrence of symptoms symptoms by relaxing the smooth muscles of the colon. was significantly higher in the placebo group than in